Rabbits which had received horseradish peroxidase (HRP) intravenously were subjected to bicuculline-induced generalized seizures of 15 min duration in order to elucidate the mechanism by which macromolecules traverse the blood- brain barrier (BBB) in specific neuroanatomically defined brain areas. As a rule, transendothelial pinocytosis at the level of arterioles was the main route of passage. In addition, tracer-filled pinocytotic vesicles were also observed in the capillaries of the hippocampus, thalamus, whereas in thalamus, hypothalamus and septum, they were present also in the endothelium of venules. Indication of an opening of the interendothelial tight junctions was found in the hypothalamus. The HRP, which had reached the neuropil due to the seizure-evoked BBB opening, accumulated in the interstitial spaces and penetrated the synaptic cleft region. Uptake of the tracer in vesicular form into presynaptic boutons, presumably excitatory ones, was observed in all brain regions; it was frequent in pallidum, hippocampus and medulla oblongata and very intense in the thalamus. Concomitant uptake in postsynaptic dendrites, was present mostly in the vicinity of boutons. Incorporation into glial processes was rare. It is concluded that blood-borne macromolecules traverse the BBB by regionally selective, transmitter-controlled pinocytotic transport and the the neuronal uptake of the foreign protein during the generalized seizures is at least partially dependent on the involvement of synapses of particular brain regions. These studies contribute to the understanding of mechanisms operative in epileptic seizures.